Effects of traditional Chinese medicine in the treatment of patients with central serous chorioretinopathy: A systematic review and meta-analysis

Several studies have reported the efficacy of traditional Chinese medicine (TCM) for central serous chorioretinopathy (CSC), while some ophthalmologists are concerned that TCM may be a risk factor for CSC as some chinese herbs contain hormonal ingredients. This study aimed to evaluate the efficacy and safety of TCM in treating patients with CSC. Randomized controlled trials (RCTs) and observational studies of TCM for CSC were searched up to July 10, 2023 on the following biological databases without language and publication time restrictions: PubMed, Ovid Medline, Embase, Cochrane Library, The Chinese National Knowledge Infrastructure Database (CNKI), Technology Periodical Database (VIP), Wanfang, and Chinese Biomedical Literature Service System (SinoMed). Review Manager V.5.4.1 and Stata 14 software were used for data analysis. Finally, thirty-eight studies were finally included including 23 RCTs and 15 cohort studies. The meta-analysis showed that compared with the routine treatment alone, the combination of TCM can not only reduce the recurrence rate (OR = 0.29, 95% CI: 0.21,0.40; I2 = 0%) and central retinal thickness (CRT) (MD = - 35.63, 95% CI: - 45.96,-25.30; I2 = 89%) of CSC, but improve patients’ best corrected visual acuity (BCVA) (SMD = 0.86, 95% CI: 0.62,1.11; I2 = 77%); additionally, it has no obvious side effects compared with routine treatment (OR = 0.72, 95% CI: 0.39,1.34; I2 = 10%). Overall, this study shows that the use of TCM does not increase the risk of CSC recurrence; on the contrary, the combination of TCM may reduce the recurrence of CSC and improve BCVA and CRT in patients with CSC compared with conventional treatment.


Introduction
Central serous chorioretinopathy (CSC) is a chorioretinal disease characterized by serous detachment of the neurosensory retina, accompanied by retinal pigment epithelium (RPE) TCM treatment with treatment in the control group were also included, while studies that combine treatment outside of TCM were excluded.In addition, studies of intravenous input and topical application of herbal medicines were excluded.Interventions in the control group contained conventional treatment measures such as medications to improve fundus microcirculation, vitamin-based supplements, PDT, anti-VEGF, and laser therapy, as well as placebo and no treatment.The recurrence rate of CSC and best corrected visual acuity (BCVA) were set as primary outcomes, and central retinal thickness (CRT) and adverse events were set as secondary outcomes.

Exclusion criteria
Studies involving any of the following were not included: 1) studies containing herbal medicines in both control and intervention groups; 2) the treatment in the intervention group included treatments out of TCM in addition to the control group interventions; 3) case series; 4) no full text; and 5) studies in which key information was unclear or unknown and no results were available after contacting the authors.

Search strategy
Relevant literature was searched in the following databases: PubMed, Ovid Medline, Embase, Cochrane Library, The Chinese National Knowledge Infrastructure Database, Technology Periodical Database (VIP), Wanfang, and Chinese Biomedical Literature Service System (SinoMed).The search time was from inception to July 10, 2023, without language and publication time restrictions.In addition, relevant web pages were also manually searched (www.clinicaltrials.gov;www.clinicaltrialsregister.eu; trialsearch.who.int) for ongoing trials or unpublished clinical trial reports.The specific search strategy can be found in S1 Table.

Data extraction
Two reviewers conducted a literature search independently (JS and SR).After screening out the duplicate documents in EndNote software, a preliminary review was carried out by reading the titles and abstracts of the retrieved documents.The literature that satisfied the inclusion and exclusion criteria was read in full to determine its eligibility for further inclusion.For eligible trials, two reviewers (LY and JW) independently extracted information based on a predesigned standardized template, including (1) study characteristics (study year, country, and study type); (2) patient characteristics, including the information of sample size, sex, age, CSC type (acute, < 6 months; chronic, � 6 months), etc; (3) details of intervention measures (TCM composition, frequency, and duration of treatment); and (4) clinical outcome indicators.Any differences between the two reviewers were resolved through communication and negotiation with an arbiter.

Quality assessment
The methodological quality of the included studies was evaluated independently by two reviewers (JS and HS) according to the Cochrane risk-of-bias tool for randomized trials (RoB 2.0) as follows [21]: randomization process, deviations from the intended interventions, missing outcome data, measurement of the outcome and selection of the reported result.For each item, we divided the research into "high", "unclear", and "low" risk of bias.The overall risk of bias for each study was evaluated based on S2 Table .The quality of observational studies was evaluated using the Newcastle -Ottawa quality assessment scale (NOS) [22].When there was insufficient information to make a judgment, we inquired about relevant information to the corresponding author via email.Any controversies were settled through consultation with the third reviewer (WS).

Data analysis
ReviewManager (RevMan) version 5.4.1 (The Cochrane Collaboration, Oxford, UK) was used for the meta-analysis.Continuous outcome variables were calculated by mean differences (MDs) or standard mean differences (SMDs) with 95% confidence intervals (CIs), and dichotomous outcome variables were calculated by combined odds ratio (ORs) with 95% CIs.When the heterogeneity of outcome variables was low (P > 0.10, I 2 < 50%), the fixed-effect model was used; otherwise, the random-effect model was used.Publication bias was evaluated visually by creating funnel plots via RevMan 5.4.1 version, as well as by conducting Egger's regression test using STATA 14.0 version (Stata Corp, College Station, TX, USA) [23].Subgroup analysis was performed by intervention type (with or without TCM contained hormone component), CSC type (acute, < 6 months; chronic, � 6 months), intervention type (PDT, laser, et al), or intervention course.Sensitivity analyses were performed to observe changes in synthetic results according to the following operations: 1) excluding low-quality studies; 2) excluding studies with small sample size; 3) excluding studies with the largest sample size; 4) excluding studies containing Chinese patent medicine; 5) or switching between fixed and random effects models.For indicators that were not sufficient for the meta-analysis, a narrative description was made [24].

Quality of evidence
The quality of the pooled evidence for all the outcomes was judged by two independent reviewers with extensive work experience as ophthalmologists (LC) and TCM practitioners (WZ) according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system [25].The strength of evidence was graded as "high", "moderate", "low" or "very low" based on five assessment items: risk of bias, inconsistency, indirectness, imprecision, and other considerations.Any controversies were settled through consultation with the third reviewer (WS).

Literature search
A total of 1826 articles were included, of which 988 studies were removed due to duplication.After reading the titles and abstracts, 360 articles remained (478 articles were removed, including 167 irrelevant articles, 189 reviews, and 122 case reports and case series).Of these, 114 used inappropriate controls, 128 lacked indicators of interest, 71 lacked key information, and 9 involved duplicate publications.Finally, 38 studies were included  (Fig 1).See S1
Interventions in the control group included 30 articles on vitamin supplements/retinal microcirculation-improving drugs, 7 articles on laser, 2 articles on PDT, and 1 article on no treatment.The follow-up period ranged from 3 months to 2 years.

Risk of bias assessment
ROB was used to evaluate the risk of bias in 23 RCTs [26, 27, 29-42, 44, 45, 50, 53-56].Eighteen studies reported randomization methods, 13 of which used random number tables [26, 30-37, 40-42, 50], two used lottery methods [29,56], and three were based on the order of attendance [53][54][55].No placebo was used in any of the studies.All studies did not mention allocation concealment, blinding of subjects, and outcome evaluation, and the risk of bias was determined to be "unclear".There was no case shedding in any of the studies.Ultimately, the overall risk of bias in 5 studies was assessed as "High" and 18 studies as "medium".Fifteen observational studies were evaluated using the NOS [28, 43, 46-49, 51, 52, 57-63], and all the patients were hospital-confirmed.One study took a prospective cohort [28], and the method of randomization was unknown.Fourteen studies used a retrospective cohort study.All studies proposed controls for age and gender factors.Follow-up was implemented in all but one study [48].Of these, 11 [43, 46, 47, 49, 51, 52, 57, 58, 60-62] performed follow-ups of sufficient duration (follow-up �1 year).Overall, 12 studies were rated as high quality (NOS �7).See Table 2 for details.
BCVA was recorded in 3 studies using the logarithm of the minimum angle of resolution (logMAR) [36,38,47], and the random-effects model showed no statistically significant difference between the TCM group and the conventional treatment group (MD = -0.02,95% CI: -0.06,0.02)(Fig 3B ).
Adverse events.Adverse events were reported in only 6 studies [26,28,29,33,42,49], mainly including nausea, gastrointestinal reactions, panic, and subcutaneous hemorrhage and hardening accompanied by subcutaneous injection of drugs.The random effects model showed that there was no statistically significant difference in the incidence of adverse events between the TCM group and conventional treatment group (OR = 0.72, 95% CI: 0.39,1.34;I 2 = 10%), regardless of whether the TCM contained hormonal components or not.(Fig 5).

Sensitivity analysis and subgroup analysis
Sensitivity analysis showed the stability of all the outcomes including the recurrence rate of CSC, BCVA, CRT, and adverse event rate.For subgroup analyses, the heterogeneity of BCVA versus CRT outcomes decreased when limiting the duration of the intervention (�2 Months), suggesting that the duration of the intervention was a source of heterogeneity.In addition, the heterogeneity of BAVC outcomes was significantly reduced when the type of restriction was an observational study.Subgroup analyses according to the type of CSC showed altered outcomes involving patients with mixed types of CSC, suggesting that the difference in recurrence rates between the TCM and conventional treatment groups was not statistically significant (OR = 0.51, 95% CI: 0.25,1.07;I 2 = 65%).See Tables 3 and 4 for details.
Narrative description.One study described SRF [38] and showed that SRF was 28.27 ± 18.52 d in the herbal group and 106.04 ± 83.38 d in the control group, which was statistically significant (p < 0.01).
Publication bias evaluation.The funnel plot based on recurrence rates is shown in Fig 6, with the majority of studies located in the upper middle of the funnel.Egger's regression test was used to detect publication bias, and the result showed P = 0.052, indicating no significant publication bias (S1 Fig).

Discussion
The present meta-analysis showed that TCM did not trigger the risk of CSC recurrence; on the contrary, compared with conventional treatment, TCM treatment could reduce the recurrence of CSC.In addition, the results of the meta-analysis suggested that TCM had the effect of reducing CRT and improving BCVA, and had no significant side effects compared with conventional treatment.However, limited by the quality of included studies, the certainty of outcomes is a concern.The use of corticosteroids is the most significant external risk factor for developing CSC, with odds ratios as high as 37:1 being reported [64].Although rare, in some cases even minimal exposure to corticosteroids exposure has been associated with an increased risk, exacerbation, and/or recurrence of CSC [65,66], suggesting that the increased risk of developing CSC is not solely dependent on the dose or mode of corticosteroid administration, but may also depend on genetic predisposition and/or an increased vulnerability to corticosteroid exposure in some individuals [9].The mechanism of corticosteroid-induced CSC may be related to the activation of both the gluco-and the mineralocorticoid (MR) receptors.As MR over-activation is pathogenic in the retina and choroid, it could mediate the pathogenic effects of corticosteroids in CSC [67].Some herbal medicines have been feared to cause recurrence and exacerbation of CSC because of their hormonal content.This study did not find evidence that herbal medicines induced CSC recurrence, even those containing hormonal components.There are several possible reasons for this: hormone-containing herbs account for a relatively small percentage of the components in the formula, and the content or activity of the hormone components is disturbed during heating and boiling or further processing [68].In addition, some herbs mostly play a hormone-like pharmacological role, such as licorice [69] and ginseng [70].Another possible reason is that Chinese medicines contain such a small amount of hormonal components that they cannot trigger significant side effects.Besides, the pharmacological actions of herbs are complex, and the interactions of multiple targets of action among individual drugs in the herbal formulas further interfere with the hormonal effects [71,72].The outcome of the meta-analysis of CRT shows that Chinese herbs could significantly reduce the thickness of retinal edema in patients with CSC, although the outcome is highly heterogeneous.Similarly, several studies have identified the absorption-promoting effects of TCM on fundus edema [14,73,74], and this process may involve multiple mechanisms.Choroidal dysfunction is considered to be the main etiology of CSC, and venous congestion, inflammation, and hemodynamic changes can lead to choroidal hyperpermeability and subsequent fluid leakage in CSC [75].TCM has been found to improve fundus microcirculation and inhibit inflammation [74,[76][77][78][79], which may reduce fluid leakage and facilitate the absorption of edema.In addition, the activation of mineralocorticoid receptors can lead to recurrence and exacerbation of CSC [67], and there have been studies showing the modulation of mineralocorticoid activity by a variety of herbal medicines, which may also be one of the mechanisms of action of TCM in the treatment of CSC [80][81][82].
Our BCVA and CRT outcomes were highly heterogeneous, and subgroup analyses showed that part of the heterogeneity came from the type of study and the duration of the treatment intervention.We noted that the included studies used 3 visual acuity counting methods, including decimal VA, 5SL, and logMAR.Among them, decimal VA and 5SL charts account for the majority of the included studies (decimal VA,18/23; 5SL, 2/23).In China, both decimal VA and 5SL charts are commonly used in screening, ophthalmology clinic.However, there are some differences between the two approaches and the logMAR recording method.Decimal charts have an irregular progression in size and are often truncated, especially in the lines testing low acuity, whereby only one or three optotypes are presented per line.Thus, the data may not follow a normal distribution, and this problem is not overcome merely by converting the data to logMAR [83].The design of the 5SL chart follows the Weber-Fechner rule, which was thought could be directly used for VA statistics and efficacy evaluation, and be essentially equivalent to the logMAR recording method [84].However, the agreement between 5SL and logMAR is not high, and the VA measured by the 5SL chart is slightly better than that by the logMAR vision chart [84,85].Thus, the different methods of recording visual outcomes may contribute to the heterogeneity of BCVA.In addition, the heterogeneity of BCVA decreased significantly when limiting the intervention to TCM alone, suggesting that the different types of intervention may also be a source of heterogeneity in BCVA outcomes.
In terms of recurrence rate, only one study included patients with chronic CSC, and the results showed no significant difference between the TCM and conventional treatment groups.However, the small sample size of the study greatly limited the certainty of this outcome.Similarly, when limiting the use of the logMAR method to document BCVA, it was found that herbal medicines did not suggest an improvement in BCVA, and this outcome remains limited by the insufficient number of studies and patients.
Our study had a comprehensive search strategy that included all the literature on herbal medicine-related treatments for CSC to the best of our knowledge.The sensitivity analysis suggested that the outcome of the meta-analysis was stable.Nonetheless, we have the following limitations: first, although we implemented an adequate and detailed search strategy, the possibility of publication bias cannot be ruled out, which means that some result values may be amplified, especially in the presence of selective reporting bias in some included studies.Second, the inclusion population of this study was all Chinese, which is restrictive for generalization to other populations.In addition, the therapeutic measures in the control group included in the study were mainly improvement of microcirculation, vitamin supplements, laser, and other therapeutic measures, of which there were fewer studies containing laser therapy and no studies involving PDT and anti-VEGF therapy, the effect of Chinese medicine in this population remains uncertain.Last, studies involving BCVA and CRT were at high risk of combined intervention bias (performance bias), inconsistency (high heterogeneity), and imprecision (small samples), limiting the quality of evidence.As a result, no evidence was highly definitive.According to the GRADE evaluation system, the quality of our evidence ranged from "moderate" to "very low" (Table 5).
Overall, our findings suggest that herbal medicines do not increase the risk of CSC recurrence; rather, the combination of herbal medicines may play a role in decreasing the rate of CSC recurrence and improving BCVA and CRT in patients with CSC compared with conventional treatment.

Moderate certainty:
We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.

Very low certainty:
We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

Explanations
Concerns about bias in the domains of allocation concealment, blinding of outcome assessment and selective reporting.

Table 5 . Summary of findings.
We are very confident that the true effect lies close to that of the estimate of the effect.